Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
2.
Mol Cancer Ther ; 20(12): 2469-2482, 2021 12.
Article in English | MEDLINE | ID: mdl-34552012

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, resistant to chemotherapy and associated with high incidence of liver metastases and poor prognosis. Using murine models of aggressive PDAC, we show here that in mice bearing hepatic metastases, treatment with the IGF-Trap, an inhibitor of type I insulin-like growth factor receptor (IGF-IR) signaling, profoundly altered the local, immunosuppressive tumor microenvironment in the liver, curtailing the recruitment of myeloid-derived suppressor cells, reversing innate immune cell polarization and inhibiting metastatic expansion. Significantly, we found that immunotherapy with anti-PD-1 antibodies also reduced the growth of experimental PDAC liver metastases, and this effect was enhanced when combined with IGF-Trap treatment, resulting in further potentiation of a T-cell response. Our results show that a combinatorial immunotherapy based on dual targeting of the prometastatic immune microenvironment of the liver via IGF blockade, on one hand, and reversing T-cell exhaustion on the other, can provide a significant therapeutic benefit in the management of PDAC metastases.


Subject(s)
Adenocarcinoma/immunology , Carcinoma, Pancreatic Ductal/immunology , Immunologic Factors/immunology , Immunosuppression Therapy/methods , Immunotherapy/methods , Animals , Humans , Mice , Neoplasm Metastasis , Tumor Microenvironment
3.
J Med Chem ; 64(15): 11129-11147, 2021 08 12.
Article in English | MEDLINE | ID: mdl-34291633

ABSTRACT

Both previous and additional genetic knockdown studies reported herein implicate G protein-coupled receptor kinase 6 (GRK6) as a critical kinase required for the survival of multiple myeloma (MM) cells. Therefore, we sought to develop a small molecule GRK6 inhibitor as an MM therapeutic. From a focused library of known kinase inhibitors, we identified two hits with moderate biochemical potencies against GRK6. From these hits, we developed potent (IC50 < 10 nM) analogues with selectivity against off-target kinases. Further optimization led to the discovery of an analogue (18) with an IC50 value of 6 nM against GRK6 and selectivity against a panel of 85 kinases. Compound 18 has potent cellular target engagement and antiproliferative activity against MM cells and is synergistic with bortezomib. In summary, we demonstrate that targeting GRK6 with small molecule inhibitors represents a promising approach for MM and identify 18 as a novel, potent, and selective GRK6 inhibitor.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , G-Protein-Coupled Receptor Kinases/antagonists & inhibitors , Multiple Myeloma/drug therapy , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , G-Protein-Coupled Receptor Kinases/metabolism , Humans , Mice , Models, Molecular , Molecular Structure , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity Relationship
4.
FASEB J ; 28(9): 4055-67, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24903273

ABSTRACT

The tyrosine kinase encoded by the MET oncogene is activated by gene mutation or amplification in tumors, which in most instances maintain addiction, i.e., dependency, to MET activation. This makes MET an attractive candidate for targeted therapies. Here we show that, in 3/3 MET-addicted human gastric cancer cell lines, MET kinase inhibition resulted in a 3- to 4-fold increased expression of the antiapoptotic small heat-shock protein of 27 kDa (HSP27, HSPB1). HSP27 increase depended on the inhibition of the MEK/ERK pathway and on heat-shock factor 1 (HSF1) and hypoxia-inducible factor-1α (HIF-1α) regulation. Importantly, HSP27-silenced MET-addicted cells underwent 2- and 3-fold more apoptosis following MET inhibition in vitro and in vivo, respectively. Likewise, in human cancer cells susceptible to epidermal growth factor receptor (EGFR) inhibition, EGFR inhibitors induced HSP27 expression and were strengthened by HSP27 suppression. In control cell lines that were not affected by drugs targeting MET or EGFR, these drugs did not induce HSP27 increase. Therefore, in cancer therapies targeting the MET pathway, the induction of HSP27 might limit the efficacy of anti-MET agents. As HSP27 increase also impairs the effectiveness of EGFR inhibitors and is known to protect cells from chemotherapeutics, the induction of HSP27 by targeted agents might strongly affect the success of combination treatments.


Subject(s)
Gene Expression Regulation, Neoplastic/drug effects , HSP27 Heat-Shock Proteins/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Stomach Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Blotting, Western , Cell Cycle/drug effects , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/drug effects , HSP27 Heat-Shock Proteins/antagonists & inhibitors , HSP27 Heat-Shock Proteins/genetics , Heat-Shock Proteins , Humans , Immunoenzyme Techniques , Mice , Molecular Chaperones , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Stomach Neoplasms/enzymology , Stomach Neoplasms/pathology , Tumor Cells, Cultured , Up-Regulation , Xenograft Model Antitumor Assays
SELECTION OF CITATIONS
SEARCH DETAIL
...